Published data show that beta amyloid vaccination can markedly reduce amyloid burdens, apparently by activating microglia to degrade amyloid. Vaccinations may also prevent certain behavioral deficits. The overall impact on the AD phenotype remains vague. Vaccination might be expected to reduce amyloid but activate microglial inflammatory cytokine production, NADPH oxidase and reactive oxygen species. This may lead to a net decrease or possibly even an increase in oxidative damage and synapse loss. In this proposal, Aim 1 will address unanswered questions about the impact of vaccination at different timepoints on aspects of inflammation while aim 2 will investigate the impact on oxidative damage and synaptic pathology that we have documented in aging APP transgenic mice. Present data suggests that vaccination may not reduce Abeta 40 and vascular amyloid. There is also a real danger that vaccination may induce vascular damage and possibly even hemorrhage. Aim 3 will assess the impact of vaccination on amyloid and soluble Abeta in different compartments, vascular amyloid and vessel damage. Finally, there are unanswered questions about the mechanisms of amyloid reduction induced by vaccination. Available data strongly support an increase in amyloid phagocytosis by microglia, but data on enhanced degradation are inconsistent with some reports showing increases and some showing no change in amyloid degradation. Aim 4 will investigate hypotheses about the mechanisms involved in vaccine induced amyloid reductions. If successful, these experiments would be expected to lead to small molecule approaches to mitigate potential harmful effects of vaccination and to conceivably enhance amyloid removal.